Medicinal chemistry involves understanding how a drug's physical and chemical properties influence its pharmacological effects. Key properties include ionization, solubility, and partitioning. A drug's ability to elicit a therapeutic response depends on how these properties affect its interaction with biological targets like proteins and enzymes. Solubility is particularly important for drug formulation, absorption, distribution, and more. Both hydrophilic and lipophilic structural features determine a drug's relative solubility in aqueous versus lipid phases. Laboratory experiments can directly measure this solubility via a compound's partition coefficient.

1. MEDICINAL CHEMISTRY
1
Unit I

2. 2

3. D EFINITION:
ÿThe ability
to elicit
of
a
a chemical compound
pharmacological/
therapeutic ef
fectis related to the inf
luence ofvarious
physical and chemical ( properties of
thatit
the chemical substance on the bio molecule
interacts with.
1)Physical Properties
Physical property ofdrug is responsible f
orits action
2)Chemical Properties
The drug react extracellularly according to simple
chemical reactions like neutralization, chelation, oxidationetc

4. Physico-chemical properties in relation to biological
action
Drug action resultsf
r
omtheinteractionofdr
ugmoleculeswit
heither
normalorabnormal physiological processes.
Dr
ugsnor
mally interactwit
ht
ar
get
s(whicht
hey areproteins,enzymes, cell
lipids, orpiecesofDNA orRNA).
Theabilityofachemicalcompoundtoelicitapharmacologic
/
t
her
apeut
icef
f
ectisr
elat
edt
o t
heinf
luenceofit
svar
iousphysicaland
chemical (physicochemical)properties
4

5. Various Physico-Chemical Properties are,
5
• Ionization of Drug
• Solubility
• Partition Coefficient
• Hydrogen Bonding
• Protein binding
• Chelation
• Bioisosterism
• Geometrical and optical isomerism

6. I onization ofdrug
6
• M ostofthe drugs are eitherweak acids or base
and can existin either ionised orunionised state.
• Ionization = Protonation or deprotonation
resulting in charged molecules.
• The ionization ofthe drug depends on its pK a &
pH .
• The rate ofdrug absorption is directly
proportional to the concentration ofthe drug at
absorbable f
orm butnotthe concentration ofthe
drug atthe absorption site.

7. • Ionization f
orm imparts good watersolubility
to the drug which is required ofbinding of
drug and receptorinteraction
• U nionized f
orm helps the drug to cross the
cell membrane.
• Eg; Barbituric acid is inactive because itis
strong acid. while, 5,5disubstituted
Barbituric acid has CN S depressantaction
because itis weak acid.
7

10. SOLUBILITY OF ORGANIC MEDICINAL
AGENTS
Importance of solubility:
(1)Formulation of the drug in an appropriate dosage
form and
(2) Bio-disposition: Disposition of drugs in the living
system after administration (absorption, distribution,
metabolism, and excretion).
Thesolubility expression: in terms of its affinity/philicity or repulsion/phobicityfor
eitheranaqueous(hydro)orlipid(lipo)solvent.

11. ♣hydrophilic.................... waterloving
♣lipophobic..................... lipid hating
♣lipophilic....................... lipid loving
♣hydrophobic.................. water hating 7

12. 8

13. 9

14. SOLUBILITY OF ORGANIC MEDICINAL AGENTS
In orderf
orachemicalcompoundtodissolveinaparticular solvent
/
medium the
compoundmustestablishattractivef
orcesbetween itselfand moleculesofthe
solvent.
ItispossibletoestimatethesolubilitypropertiesofanOMA(hydrophilicvs.
lipophilic)byexaminingthestructureofthe drugsandnotingwhet
heritsstructural
f
eaturespromoteaf
f
inityf
or aqueousor lipidmedia.
Themostimportantintermolecularattractivef
orces(bonds)thatareinvolvedinthe
solubilizationprocessare:
10

15. δ
-
11
N :
δ+
H O
δ
-
O
δ+
H
C
H O
δ+
H
O
δ
-
H
Themostimportantintermolecularattractiveforces(bonds)
:thatareinvolved inthe solubilizationprocessare
1. Van der Waals Attraction
■weakestintermolecularforce(0.5-1.0kcal/mole)
■electrostatic
■occursbetweennonpolargroups(e.g.hydrocarbons)
■highlydistanceandtemperaturedependent
2. Dipole- Dipole Bonding
■stronger (1.0 to 10kcal/mole)
■occurselectrostaticallybetweenelectrondeficientandelectronexcessive/richatoms(dipoles)
■hydrogenbondingisaspecificexampleofthisbondingandservesasaprime contributor to
hydrophilicity

16. H
O δ- O H
+
N H
H C δ+
O - H
O
3. Ionic Bonding
■electrostaticattractionbetweencationsandanions
■commonininorganiccompoundsandsaltsoforganic
molecules
■relativelystrong(5kcal/mole) N+
O
H C l
- C N a+
O -
4. Ion-Dipole Bonding
■electrostaticbetweenacation/anionandadipole
■relatively strong (1-5kcal/mole)
■lowtemperatureanddistancedependence
■importantattractionbetweenOMAsandH2O
12

17. Solubility Prediction
13
¬Therelativesolubilityofadrugisafunctionof thepresenceof
bothlipophilicandhydrophilic features within its structure,
which serve to determ
inetheextentofinteractionoftheOMAw
ith
lipid and/or aqueousphases.
¬Therelativesolubilityofa drugcanbe determinedinthe
laboratory,i.e.the partition coefficient [P;theratioofthe
solubilityofthe
compoundinanorganicsolventtothesolubilityof thesamecompoundin
anaqueousenvironment(i.e., P=[Drug]lipid/ [Drug]aqueous). P is
often expressed as a logvalue.

18. Solubility Prediction
A mathematical procedures also have been developedtoestimate
therelativesolubilityofan organic molecule based upon
differential contributionsofvariousstructuralfeaturestooverall
solubility.
Forexample,therelativesolubilityofadrugisthesumof the
contributions of each group and substituent to overall solubility.
Example:
Examinationofthestructureofchloramphenicol
(indicatesthepresenceofbothlipophilic(nonpolar)andhydrophilic
(polar)groupsandsubstituents.
14

19. Solubility Prediction
L ip o p h ilic
15
H y d r o p h i l i c
H y d r o p h i l i c L ip o p h ilic
O 2 N C H C l 2
O H O
C H C H N H C
C H 2 O H
C h l o r a m p h e n i c o l
H y d r o p h i l i c

20. Solubility Prediction
1.Laboratory Estimation of Relative Solubility
Therelativesolubilityofanorganiccompoundismeasuredbydeterminingtheextentofitsdistributionintoan
aqueoussolvent(usuallypH7.4buffer)anda lipidsolvent(usuallyn-octanol).Theseexperimentsgenerateavalue,
P,the partition coefficient for that particular compound.
C o n c . o f c o m p u n d s i n
C 8 H 1 6 O H
P artitio n co effici en t =
C o n c . o f c o m p u n d s i n H 2 O
18
16

21. 19

22. 31

23. 32

24. 33

25. 34

26. 35

27. 36

28. 37

29. 38

30. 39

31. 40

32. 41